Matching donor and recipient based on predicted indirectly recognizable human leucocyte antigen epitopes

Geneugelijk, Kirsten; Spierings, Eric

doi:10.1111/iji.12359

Cited by 36 publications

(38 citation statements)

References 80 publications

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“…In parallel with B cell epitopes, attention has also been focused on T cell epitopes, specifically, those associated with donor-derived HLA molecules presented by HLA class II on recipient antigen presenting cells (20). T cell epitopes are recognized by the T cell receptor of CD4+ T cells at the first step toward DSA production via T-dependent B cell activation (Supplementary Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Analysis of T and B Cell Epitopes to Predict the Risk of de novo Donor-Specific Antibody (DSA) Production After Kidney Transplantation: A Two-Center Retrospective Cohort Study

et al. 2020

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Risk prediction of de novo donor specific antibody (DSA) would be very important for long term graft outcome after organ transplantation. The purpose of this study was to elucidate the association of eplet mismatches and predicted indirectly recognizable HLA epitopes (PIRCHE) scores with de novo DSA production. Our retrospective cohort study enrolled 691 living donor kidney transplantations. HLA-A, B, DRB and DQB eplet mismatches and PIRCHE scores (4 digit of HLA-A, B, DR, and DQ) were determined by HLA matchmaker (ver 2.1) and PIRCHE-II Matching Service, respectively. Weak correlation between eplet mismatches and PIRCHE scores was identified, although both measurements were associated with classical HLA mismatches. Class II (DRB+DQB) eplet mismatches were significantly correlated with the incidence of de novo class II (DR/DQ) DSA production [8/235 (3.4%) in eplet mismatch ≤ 13 vs. 92/456 (20.2%) in eplet mismatch ≥ 14, p < 0.001]. PIRCHE scores were also significantly correlated with de novo class II DSA production [26/318 (8.2%) in PIRCHE ≤ 175 vs. 74/373 (19.8%) in PIRCHE ≥ 176, p < 0.001]. Patients with low levels of both class II eplet mismatches and PIRCHE scores developed de novo class II DSA only in 4/179 (2.2%). Analysis of T cell and B cell epitopes can provide a beneficial information on the design of individualized immunosuppression regimens for prevention of de novo DSA production after kidney transplantation.

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Section: Introductionmentioning

confidence: 99%

Analysis of T and B Cell Epitopes to Predict the Risk of de novo Donor-Specific Antibody (DSA) Production After Kidney Transplantation: A Two-Center Retrospective Cohort Study

et al. 2020

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“…Clearly, investigating the immunogenicity of structural molecular mismatches is population dependent and impacted by additional variables (eg, BCR‐repertoire, TCR‐repertoire, PIRCHE II 21‐23 ).…”

Section: Discussionmentioning

confidence: 99%

Toward defining the immunogenicity of HLA epitopes: Impact of HLA class I eplets on antibody formation during pregnancy

Hönger

Niemann²,

Schawalder

et al. 2020

HLA

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Eplets are functional units of structural epitopes on donor HLA, potentially recognized by complementarity‐determining regions of the paratope of the recipients' B‐cell receptors or antibodies (Ab). Their individual immunogenicity is poorly described, yet this feature would be of clinical importance for pretransplant risk assessment. The aim of this study was to determine the relative immunogenicity of HLA class I eplets in the pregnancy setting, where mismatched eplets are present on paternal HLA antigens of the unborn child. One hundred fifty‐nine predominantly Caucasian mothers giving birth at the University Hospital Basel and their first newborns were HLA‐typed at high‐resolution by next‐generation sequencing (NGS) (NGSgo Workflow and NGSengine from GenDx; sequencing with a Miseq from Illumina) and eplets were determined using HLAMatchmaker. HLA class I specific IgG Ab was assessed in maternal sera drawn immediately after full‐term delivery, by OneLambda LABScreen single antigen ibeads. The Ab profile was subsequently evaluated for eplet‐associated patterns. All 72 currently Ab‐verified HLA class I eplets were examined for their immunogenicity according to the frequency of child‐specific HLA Ab (CSA) directed against their structures. Four hundred twelve of 477 (86.4%) paternal HLA‐A, ‐B or ‐C alleles were mismatched. CSA were present in 46 mothers (28.9%), directed against 80 (19.4%) of these mismatches. The 10 most immunogenic eplets were 62GK, 145KHA, 144TKH, 62GE, 107W, 80I, 82LR, 41T, 127K, 45KE with immunogenicity rates between 45.8% and 27.3%. This pregnancy study also identified five non‐reactive eplets: 62RR, 76ESN, 80TLR, 156DA, 163RW. Based on our results, immunogenic hot and cold spots on the surface of HLA class I molecules were localized and visualized on 3D models. This study strengthens the presumption that different eplets represent different immunogenic potentials. Validation of these results in the clinical transplant setting is an essential next step in identifying those eplets representing a particularly high‐risk potential.

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“…Theoretically, high PIRCHE-II numbers are associated with a high level of CD4+ T cell alloreactivity. PIRCHE-II specific CD4+ T cells may impact transplant outcome via two ways [reviewed in (23)]: CD4+ T-helper cells may, after indirect recognition of mismatched HLA, provide help to mismatched HLA-specific CD8+ cytotoxic T cells, and consequently induce alloreactive responses via these CD8+ T cells. On the other hand, PIRCHE-II specific CD4+ T cells may play a role in the formation of HLA-specific antibodies by providing B cell help.…”

Section: Discussionmentioning

confidence: 99%

Exploratory Study of Predicted Indirectly ReCognizable HLA Epitopes in Mismatched Hematopoietic Cell Transplantations

et al. 2019

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HLA-mismatches in hematopoietic stem-cell transplantation are associated with an impaired overall survival (OS). The aim of this study is to explore whether the Predicted Indirectly ReCognizable HLA-Epitopes (PIRCHE) algorithm can be used to identify HLA-mismatches that are related to an impaired transplant outcome. PIRCHE are computationally predicted peptides derived from the patient's mismatched-HLA molecules that can be presented by donor-patient shared HLA. We retrospectively scored PIRCHE numbers either presented on HLA class-I (PIRCHE-I) or class-II (PIRCHE-II) for a Dutch multicenter cohort of 103 patients who received a single HLA-mismatched (9/10) unrelated donor transplant in an early phase of their disease. These patients were divided into low and high PIRCHE-I and PIRCHE-II groups, based on their PIRCHE scores, and compared using multivariate statistical analysis methods. The high PIRCHE-II group had a significantly impaired OS compared to the low PIRCHE-II group and the 10/10 reference group (HR: 1.86, 95%-CI: 1.02–3.40; and HR: 2.65, 95%-CI: 1.53–4.60, respectively). Overall, PIRCHE-II seem to have a more prominent effect on OS than PIRCHE-I. This impaired OS is probably due to an increased risk for severe acute graft-vs.-host disease. These data suggest that high PIRCHE-II scores may be used to identify non-permissible HLA mismatches within single HLA-mismatched hematopoietic stem-cell transplantations.

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Matching donor and recipient based on predicted indirectly recognizable human leucocyte antigen epitopes

Cited by 36 publications

References 80 publications

Analysis of T and B Cell Epitopes to Predict the Risk of de novo Donor-Specific Antibody (DSA) Production After Kidney Transplantation: A Two-Center Retrospective Cohort Study

Analysis of T and B Cell Epitopes to Predict the Risk of de novo Donor-Specific Antibody (DSA) Production After Kidney Transplantation: A Two-Center Retrospective Cohort Study

Toward defining the immunogenicity of HLA epitopes: Impact of HLA class I eplets on antibody formation during pregnancy

Exploratory Study of Predicted Indirectly ReCognizable HLA Epitopes in Mismatched Hematopoietic Cell Transplantations

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